Cardiovascular disease is one of the leading causes of death worldwide. It is estimated that over 70 million people in the United States alone suffer from a cardiovascular disease, such as hypercholesterolemia, myocardial infarction, and coronary artery disease. Heterozygous familial hypocholesterolemia is a common genetic disorder, with a prevalence of 1/500 that leads to elevated low-density lipoprotein cholesterol (LDL-C) in circulation, and is associated with increased risk of coronary artery disease and myocardial infarction.
There is compelling evidence from population-based data and clinical trials that LDL-C reduction is an effective strategy for preventing coronary artery disease, slowing its progression or reducing damage (Grundy et al., Circulation, 2004, 110, 222-239). Statins are efficacious LDL-C lowering agents that represent the current therapy of choice. Despite the widespread use of statins, almost half a million people die from myocardial infarction each year in the United States alone. Recent surveys have shown that patients who are at the highest cardiovascular risk are also the ones that fail more often to achieve their therapeutic goal, in particular diabetics (Davidson et al., Am. J. Cardiol. 2005, 96, 556-563). Some patients also require larger reductions of LDL-C due to their high baseline levels, like those with familial hypercholesterolemia. A substantial proportion of patients are also intolerant to statin therapy. Therefore, there is a critical need for additive or replacement therapy to statins for improved treatments for cardiovascular diseases and related disorders.